The role of lateral hypothalamic neurotensin neurons in adaptive energy balance

The lateral hypothalamic area (LHA), receives cues of energy and fluid status from the body and coordinates appropriate feeding, drinking and activity (e.g. adaptive responses) to ensure survival. The LHA contains many distinct populations of neurons, however, and it remains unclear how each of these contribute to energy balance. Here we sought to understand how LHA neurons expressing the neuropeptide neurotensin (LHA Nts neurons) coordinate distinct behaviors necessary for adaptive response and control of body weight. While activation of most LHA Neurons increases both feeding and drinking, activation of LHA Nts neurons specifically promotes drinking but reduces feeding. LHA Nts neurons may exert these divergent actions via distinct circuits, as they have been shown to modulate dopamine (DA) signaling and local orexin (OX) neurons. Consistent with this, we have distinguished two projection-specific and molecularly distinct subsets of LHA Nts neurons. One subset co-expresses Nts and the long form of the leptin receptor (LepRb), is activated by leptin and projects to the ventral tegmental area (VTA) and substantia nigra compacta (SNc); we refer to these as NtsLepRb neurons. A separate subset of LHA Nts neurons lacks LepRb, is activated by dehydration and does not project to the VTA or SNc; we refer to these as Nts Dehy neurons. Intriguingly, however, we found all LHA Nts neurons are similar in that they express the inhibitory neurotransmitter, GABA. We next investigated the role of the NtsLepRb subpopulation for adaptive response by studying mice lacking leptin signaling via Nts LepRb neurons. Loss of leptin regulation only via NtsLepRb neurons induced obesity, blunted adaptive response to leptin and to ghrelin (a hormonal activator of OX neurons) and dysregulated DA signaling. Finally, we defined the necessity of LHA Nts neurons for energy balance by genetically ablating or chemogenetically inhibiting them in adult mice. Prolonged loss of LHA Nts neurons decreased drinking, locomotor activity and deranged OX expression in target neurons that led to increased adiposity. By contrast, LHA Nts inhibition preserved OX expression but still blunted locomotor activity. Together these data suggest that LHA Nts neurons modulate physical activity that is not dependent on OX, but that the LHA Nts→OX circuit is necessary for regulation of drinking and adiposity. Collectively, our data show that LHA Nts neurons are necessary for regulation of adaptive energy balance, and that distinct subpopulations of LHA Nts neurons may control ingestive and locomotor behavior via OX-dependent and independent pathways. This work suggests that there may be unique LHA Nts circuits to regulate drinking, motivated feeding ingestive disorders such as obesity, anorexia nervosa, psychogenic polydipsia and dehydration.